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New Approches towards the Anti-HIV chemotherapy

2.
• Viruses are small infectious agents consisting essentially of nucleic acid(either RNA or DNA) enclosed in a protein coat called capsid.• The coat plus the nucleic acid core is termed as the nucleocapsid.• Some viruses have, in addition, a lipoprotein envelope, which may containantigenic viral glycoproteins, as well as host phospholipids acquired whenthe virus nucleocapsid buds through the nuclear membrane or plasmamembrane of the host cell.• Certain viruses also contain enzymes that initiate their replication in the hostcell.• The whole infective particle is termed as a virion. In different types ofviruses the genome may be double or single stranded.2

3.
• Viruses are intracellular parasites with no metabolic machinery of their own.• In order to replicate they have to attach to and enter a living host cell-animal, plant or bacterial and use its metabolic processes.• The binding sites on the virus are polypeptides on the envelope or capsid.• The receptors on the host cell, to which the virus attaches, are normalmembrane constituents like receptors for cytokines, neurotransmitters orhormones, ion channels, integral membrane glycoproteins, etc.Virus function and life historyVirus function and life history3

4.
• Viral DNA enters in the host cell nucleus, transcription of this viral DNAinto mRNA by host cell RNA polymerase followed by translation of themRNA into virus-specific proteins.• Some of these proteins are enzymes that synthesize more viral DNA aswell as proteins of the coat and envelope.• After assembly of coat proteins around the viral DNA, complete virionsare released by budding or after cell lysis.Condit, R. C.: Principles of virology. In Knipe, D. M.; Howley, P. M. (eds): Fundamental Virology, LipincottWilliams & Wilkins, 4th ed., 2001, pp. 19.Replication in DNA virusesReplication in DNA viruses4

5.
• Enzymes in the virion synthesize its mRNA or the viral RNA serves as itsown mRNA.• This is translated into various enzymes, including RNA polymerase (whichdirects the synthesis of more viral RNA) and also into structural proteins of thevirion.• Assembly and release of virions occurs as explained above.Replication in RNA virusesReplication in RNA viruses5

6.
• The virion in retroviruses contains a reverse transcriptase (virus RNA-dependent DNA polymerase), which makes a DNA copy of the viral RNA.• This DNA copy is integrated into the genome of the host cell and it isthen termed a provirus.• The proviral DNA is transcribed into both new genomic RNA andmRNA for translation into viral proteins.• The completed viruses are released by budding and many can replicatewithout killing the host cell.Replication in retrovirusesReplication in retroviruses6

8.
 HIV-1 subtype B is primarily responsible for the AIDS in North Americaand Western Europe.• HIV-2 is less prevalent, less pathogenic & slow progression to AIDS andcause lymphadenopathy.. Found in west Africa & India. Origin of HIV:1. HIV-1 from cross-species transmission (zoonosis) of a chimpanzee virus tohuman.2. HIV-2 from cross-species transmission of a sooty mangabey virus.• HIV discovered in 1984 by - Luc Montagneir - Pasteur Institute• HIV is a retrovirus that infects cells of the human immune system (mainlyCD4 positive T cells and macrophages) & destroys or impairs their functionwhich results in the progressive depletion of the immune system, leading toimmune deficiency‘ and AIDS.8

10.
• HIV has following types of cgenes encoding for structural proteins. The gag gene provides the physical infrastructure of the virus; The pol provides the basic enzymes by which retroviruses reproduce; The env gene supplies the proteins essential for viral attachment and entryinto a target cell.• The accessory proteins tat, rev, nef, vif, vpr, and vpu enhance virusproduction. tat and rev are essential for viral replication.• A mutation causes the production of alternate accessory protein, from thefusion of tat, rev, and env in some HIV.The gp120 and gp41 proteins, both encoded by the env gene, enable thevirus to attach to and fuse with target cells to initiate the infectious cycle.15. Mehannna, A. S. Rational of Design of Anti-HIV Drugs, Abraham, D. J.,Burger’s Text Book of MedicinalChemistry Drug Discovery, A John Wiley and Sons, Inc., 6th ed, 2003, 5, 461.HIV genomeHIV genome10

22.
• It targets T4-lymphocyte, a white blood cell that has a central rolespecifically the CD-4 helper T-cell.• HIV starts its replication cycle in the host cell with the help of theenzyme Reverse Transcriptase• Fall from a normal value of 800-1300 cells/cm2 of blood to below 200which may give threatening illness.• The suppressed immune system leaves the patient vulnerable to the so-called opportunistic infections by agents that would not harm a healthyperson.• The most common of such infections is pneumonia caused byPneumocystis carinii which cause most of the clinical complicationsFauci, A. S. The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science, 1988, 239,617-622.Cellular picture of the infectionClinical picture of the infectionImmunosuppressive effect22

23.
• It is observed in the brain , independent of the immunodeficiency are anabnormal proliferation of the glial cells that surround the neurons and lesionsresulting from loss of white matter.• This can give rise to a neurological symptoms such as dementia and multiplesclerosis.• With HIV virus there is an increased risk of at least three types of humantumors. Kaposis sarcoma a rare tumor of blood vessel tissue in the skin or internalorgans. carcinoma including skin cancer which are often seen in the mouth or rectumof infected homosexuals. B-lymphomas (tumors originating in B-lymphocytes).Neurological effectCarcinogenic effects23

27.
• Galanthus nivalis (GNA) and Hippeastrum hybrid (HHA) ,the plant lectinsderived from GNA (Snowdrop) and HHA (Amaryllis) were shown tointerrupt the viral entry process by interfering with the viral envelopeglycoprotein gp120.• When HIV-1 was made resistant to GNA and HHA, several amino acidchanges were noted in gp120 but not gp41; occurred at the N-glycosylationsites (at the S or T residues).• They are used as topical microbicides for the prevention of the sexualtransmission of HIV infection.2. Virus Attachment Inhibitors2. Virus Attachment Inhibitors27

28.
• CyanovirinA potential microbicide to prevent the transmission of HIV and AIDS ,isolated from the cyanobacterium Nostoc ellipsosporum.• Cyanovirin-N has a uniquely high affinity for gp120: it impairs both CD4-dependent and -independent binding of gp120 to thetarget cells, it blocks CD4-induced binding of gp120 with CXCR4, and it dissociatesbound gp120 from target cells.• The aglycons of the glycopeptide antibiotics vancomycin, teicoplanin, anderemomycin, were found to display activity against HIV-1, HIV-2, andMoloney murine sarcoma virus at the lower concentration range.28

29.
• The Teicoplanin aglycon , interferes with viral entry, probably at the virusadsorption step, because their anti-HIV activity was lost if added at 1-2 hafter infection.• Glycopeptide antibiotic aglycon derivatives could be envisaged aspotential lead compounds for application as microbicides against sexualHIV transmission.29

30.
• BMS- 378806 : A new class of HIV-1 attachment inhibitors [prototype: 4-benzoyl-1-[4-methoxy-1H-pyrrolo[2,3-b]- pyridin-3-yl)oxoacetyl]-2-(R)-methylpiperazine (BMS- 378806) (4)] that interferes with CD4-gp120interactions.• It binds directly to gp120 at a stoichiometry of approximately 1:1, with abinding affinity similar to that of soluble CD4.NNHONNOOCH3CH3OBMS-378806430

32.
• BMS-488043 : This Virus attachment inhibitors may be effective in vivoin HIV-1-infected patients (5), which is structurally closely related toBMS- 378806 .• BMS- 488043 is assumed to bind to the HIV-1 glycoprotein gp120 and toinduce or block conformational changes in the gp120.• The compound was well tolerated, and no serious adverse events werenoted.NNHONNOOCH3OBMS-4880435OCH332

33.
• To enter the cells following binding with the CD4 receptor, the HIVparticles must interact, again through the viral envelope glycoproteingp120, with the CXCR4 or CCR5 coreceptor.• CXCR4 is the coreceptor for Tlymphotropic (or X4) HIV strains, whereasCCR5 is the coreceptor for macrophage (M)-tropic (or X5) HIV strains.• CXCR4 normally functions as the receptor for the chemokine SDF-1(stromal cell derived factor), and CCR5 does so for RANTES (regulatedupon activation, normal T-cell expressed, and secreted) and MIP-1R and-1‚ (macrophage inflammatory proteins), and accordingly, thesechemokines inhibit the infectivity of X4 and X5 HIV strains, respectively.3. CXCR4 and CCR5 Antagonists3. CXCR4 and CCR5 Antagonists33

35.
• During phase I clinical studies AMD3100 caused a significantenhancement of the white blood cells (WBC) counts in human volunteers.• It mobilize hematopoietic stem cells from the bone marrow into thebloodstream, and because this effect proved synergistic with the action ofG-CSF (granulocyte-colony stimulating factor), so AMD3100 is now beingpursued (in phase II clinical studies) for stem cell mobilization andtransplantation in patients with multiple myeloma or non-Hodgkinlymphoma.• CXCR4 antagonists such as AMD3100 are able to suppress in vivoreplication of X4 or dualtropic X4/R5 HIV strains.35

36.
• Structure-activity relationship (SAR) studies revealed that the bis-macrocyclic structure is not an absolute prerequisite for anti-HIV activity.• For example: AMD3465 (7), an AMD3100 derivative ,proved to be aspotent, as AMD3100 as both a CXCR4 antagonist and inhibitor of X4 HIVstrains.• Also, KRH-1636 (8), another CXCR4 antagonist, with anti-HIV activitysimilar to that of AMD3100.• KRH-1636 appears to be duodenally absorbable, at least in rats, whichmeans that it may be orally bioavailable.N NHNHHNNHAMD34657NNHOHNONHCH3NHH2N NHNKRH-1636836

37.
• TAK-779 (9): The CCR5 antagonists, the quaternary ammonium derivativewas the first nonpeptidic molecule which block the replication of the M-tropic R5 HIV-1 strains (in the nanomolar concentration range) byinteraction with CCR5.• The binding site for TAK-779 has been identified within thetransmembrane (TM) helices 1, 2, 3, and 7 of CCR5.23• TAK-779 is not orally bioavailable and provokes irritation at the injectionsite.H3COHNNCH3CH3OCl-TAK-779937

39.
• Spirodiketopiperazine E913 (12).• E913 specifically blocks the binding of MIP-1R to CCR5, the MIP-1R-elicited Ca2+ flux, and the replication of both laboratory and primary R5HIV-1 strains, as well as various multidrug-resistant monocyte/ M-tropicR5 HIV-1 strains.• From the spirodiketopiperazine class of compounds, E913 was recentlyquoted as binding only partially to CCR5 while exhibiting much greateranti-HIV activity.OONNHNOO39

41.
• 1,3,4-trisubstituted pyrrolidine : CCR5 receptor antagonists have possessoral bioavailability and/or potent anti-HIV activity.• A representative congener of this 1,3,4- trisubstituted pyrrolidine series is14. The compound’s site of interaction with CCR5 has been mapped to acavity, near the extracellular surface, formed by the TM helices 2, 3, 6, and7.NNO213451,3,4-Trisubstituted pyrrolidine1441

42.
• CMPD 167, CCR5 antagonists are efficacious in vivo against CCR5-usingvirus strains, designated previously as MRK-1 (15).• This compound caused a rapid and substantial (4- to 200-fold) decrease inplasma viremia in rhesus macaques chronically infected with simianimmunodeficiency virus (SIV).• It is used as a topical microbicide to prevent HIV-1 sexual transmissionbecause viral replication could be partially inhibited by it.H3CCH3H3COCH3NNNCH3FMRK-1CMPD 1671542

43.
• The interaction of the X4 or R5 HIV-1 envelope gp120 with thecoreceptors CXCR4 or CCR5, respectively, is followed by a spring-loadedaction of gp41 that then anchors through its amino terminus into the targetcell membrane and, in doing so, initiates the fusion of the viral envelopewith the cellular plasma membrane.• During the process, hydrophobic grooves on the surface of the coiled coilgp41 ectodomain become available for binding with extraneous inhibitors,that are virus cell fusion inhibitors.4. Virus-Cell Fusion Inhibitors4. Virus-Cell Fusion Inhibitors43

45.
• Drawbacks of Enffuvirtide Enfuvirtide has to be administered twice daily by subcutaneous injection.This inevitably leads to injection- site reactions including erythema,induration, and nodules, and cysts. Another problem is the production cost for a 5000 Da molecular masspeptide such as enfuvirtide.51 Even enfuvirtide-insensitive HIV-1 variants may exist in an enfuvirtide-naive population, and this may allow virus escape from drug.45

46.
• Tris-functionalized 3,2’,2’’-terphenyl derivatives (17) could serve aseffective mimics of the exposed N-helical regions of the transient gp41intermediate and thus potentially trap this structure prior to the six-helixbundle formation, which is required for virus-cell fusion.• Compound 17 was found to inhibit HIV-1 mediated cell-to cell fusion butonly at a relatively high concentration (IC50 15 μg/mL).OOHOCH3CH3CH3H3CCH3H3CHOOTerphenyl derivative1746

49.
• Emtricitabine can be conveniently administered as a once-daily dose of200 mg for long term clinical use in HIV-1-infected individuals.• In studies through 60 weeks, once daily emtricitabine, combined withonce-daily didanosine and efavirenz, demonstrated durable and superiorvirologic efficacy and tolerability, compared to twice-daily stavudine andonce-daily didanosine and efavirenz.SOHONNNH2FOEmtricitabine [(-)FTC]18 49

50.
• Emtricitabine has been considered an “ideal drug candidate” because It shows synergism with other antiretrovirals, Excellent tolerability, A long intracellular half-life (supporting the once-daily dosing), and, In comparison with lamivudine, 4- to 10-fold higher in vitro potencyagainst HIV.50

52.
• The nucleotide reverse transcriptase inhibitors (NtRTIs) such as Adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)] and Tenofovir [(R)-9-(2- phosphonylmethoxypropyl)adenine (PMPA)]are already equipped with a phosphonate group and, therefore, only needtwo phosphorylation steps to be converted to the active metabolites(PMEApp and PMPApp, respectively).• The metabolites then serve as alternative substrates in the reversetranscriptase reaction, where upon their incorporation they act as chainterminators.6. Nucleotide Reverse Transcriptase Inhibitors(NtRTIs)6. Nucleotide Reverse Transcriptase Inhibitors(NtRTIs)52

53.
• The NtRTIs Adefovir and Tenofovir are active not only against HIV butalso against hepatitis B virus (HBV), because HBV uses for its replicationa reverse transcriptase that is quite similar to that of HIV.• They have been officially approved, in their oral prodrug forms Adefovirdipivoxil [bis( pivaloyloxymethyl )-PMEA, Hepsera] (22) and Tenofovirdisoproxil [bis( isopropyloxycarbonyloxymethyl )- PMPA] fumarate(Viread) (23), for the treatment of HBV and HIV infections, respectively.NNNNOPOOONH2OH2COH2CCCOO(H3C)3C(H3C)3CAdefovir dipivoxil22NN NNOPOOONH2OH2COH2CCCOOOOTenofovir disoproxil fumarate23H3C(H3C)3C(H3C)3CHOOCCOOH53

54.
• Both the d4T (Stavudine) and TDF (Tenofovir) arms showed a similar,high virological response. However, lipid abnormalities (increase intriglyceride and cholesterol levels) were significantly lower in the TDF armthan in the d4T arm.• Also, the toxicities (peripheral neuropathy, lipodystrophy, lactic acidosis,pancreatitis) associated with mitochondrial dysfunction through week 96were markedly lower in the TDF arm than in the d4T arm, while both armsshowed a similar renal safety profile.• Although in an animal model for HIV transmission through breast-feedingtopical administration of lowdose TDF did not protect infant macaquesagainst multiple oral exposures of simian immunodeficiency virus (SIV),54

55.
• Another indication for the clinical use of tenofovir disoproxil fumarate is(lamivudine-resistant) chronic hepatitis B in HIV/HBV- coinfectedpatients.• Several studies have demonstrated that TDF is very effective in reducingHBV DNA levels in HIV/HBV- coinfected patients carrying either wild-type or 3TC-resistant [YMDD variant (rt M204I/V)] HBV.• Noteworthy is that TDF treatment for 12 months in patients coinfectedwith HIV and 3TC-resistant HBV was not associated with the emergenceof HIV- or HBV-specific resistance mutations.55

56.
• More than 30 structurally different classes of compounds have beenidentified as NNRTIs, that are targeted at a specific, allosteric (i.e.,nonsubstrate binding) site of the reverse transcriptase.• The “first-generation” NNRTIs are notorious for rapidly eliciting virusdrug resistance, especially when used singly.• The most common mutations occurring in the clinical setting following theuse of NNRTIs are K103N and Y181C.• Therefore, attempts have been made to develop “second-generation”NNRTIs that are resilient to such drug resistance mutations.• “first-generation” NNRTIs are Nevirapine and Delavirdine while“Second-generation” NNRTIs are Efavirenz .7. Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTIs)7. Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTIs)56

57.
• DAPY derivatives1. TMC 125 (Etravirine) (27) is an investigational NNRTI with potentactivity against HIV-1 strains resistant to the currently available NNRTIs.• It is under the advance clinical development.NONN NHNBrNH2Etravirine (Tmc125)2757

58.
2. Rilpivirinemore active than NVP, EFV and dapivirine against wild-type HIV-1and all single and double mutants tested .• E-form was superior in terms of antiviral activity with respect tothe corresponding Z-isomer.• Rilpivirine was not mutagenic,no relevant side effects, had noeffect on cardiovascular, pulmonary, electrophysiological andbehavioral parameters in dog.• It is also under the advance clinical development.HNNN NHNRilpivirineCN58

59.
• Dihydropyrazinones• The cyano substituent in the 4-position of the aniline moiety was theoptimal choice,• The presence of a 6-methyl group in the dihydropyrazinone ringcause a favorable effect on activity against mutants.• Introduction of methyl substituents on the benzene ring and atposition- 6 of the dihydropyrazinone ring on the left wing increasedthe activity against both HIV wild-type and drug-resistant mutants.• Compounds with X = SO2 were slightly superior to those with X = S,which was only confirmed for the Y181C mutation.NNNHXRR1OR2R335216459

60.
• Benzophenones• These compounds proved to be much more potent than NVP andDLV, and equivalent to EFV against both wild-type HIV-1 and theY181C mutant strain.R1R2OClOOHNSO2NH23 GW4511 R1=CF3, R2 =F24 GW4751 R1=H, R2=CNF3CFOClOOHN25 GW3011O SO2NH60

61.
• 2-Quinolones• The quinolones were demonstrated to be potent inhibitors of wild-type (HIV-1 IIIB) and NVP-resistant strains in MT-4 cell assays.• R = F; Cl as substituents were optimal for antiviral activity in MT-4cells.• Replacement of R with CH3 and OCH3, led to much less activecompounds.• Introduction of a cyclopropylethynyl group as the R2 substituent ledto the more potent compoundsNHXCl RO61

62.
• Indolyl aryl sulfone• The iodole derivatives bearing the 3-[(3,5-dimethylphenyl) sulfonyl]moiety (52) displayed high activity and selectivity not only againstthe HIV-1 wild-type strain, but also against the Y181C and K103N-Y181C viral variants and the EFV-resistant (EFVR) mutant K103R-V179D-P225H.HNClONH2SO2R1R2R362

63.
• Capravirine analogues• Capravirine retained activity against HIV-1 strains carrying the K103Nmutation in their reverse transcriptase.• Replacement of ethyl in position-4 of the imidazole nucleus with aniso-propyl group led to more potent derivatives.• The activity of the compounds was also affected by the group at the5-position of the imidazole ring in the order 3,5-(CH3)2-phenyl >cyclohexyl > phenyl group• The alkoxymethyl substituent at the 1-position of imidazole ringshowed higher activity than compounds containing a 4-pyridylmethylgroup at the same position.SNNOOH2NCH3H3CClClNCapravirine (S-1153,AG1549)251234563

64.
• Pyridones• in vitro activity profile of these new molecules, and in particular ofcompound 118, was better than that of EFV.HNXON111 X= H2112 X = OHNXON117 X= O118 X = H2CN64

65.
• Integration of the proviral DNA into host cell chromosomal DNA is anessential step in the viral replication cycle.• This process is mediated by the viral integrase, and because there is nocellular homologue for this enzyme, it has been considered an attractivetarget for HIV therapeutics.• Numerous small-molecule HIV-1 integrase inhibitors have been described,the two most predominant classes of inhibitors being the catecholcontaining hydroxylated aromatics and the diketo acid containingaromatics.8. HIV Integrase Inhibitors8. HIV Integrase Inhibitors65

66.
• Catechol containing hydroxylated aromatics• An example is L- chicoric acid (28).• Integrase was identified as the molecular target for the action of L- chicoricacid, since a single amino acid substitution (G140S) in the integraserendered the corresponding HIV-1 mutant resistant to L- chicoric acid.• It was later shown that the G140S mutation confers resistance not only toL- chicoric acid but also to the diketo acid L-731,988 and furthermoreattenuates the catalytic activity of the enzyme.HOHOOOOOHOOOOHOHL-Chicoric acid28HO66

67.
• In our hands, however, HIV-1 integrase carrying the G140S mutationappeared to be as sensitive to the inhibitory effect of L- chicoric acid as thewild-type integrase.• Upon repeated passages of the virus in the presence of L- chicoric acid,mutations were found in the viral envelope glycoprotein gp120 but not inthe integrase.• HIV strains resistant to polyanionic compounds showed cross-resistance toL- chicoric acid, and time-of addition experiments further confirmed thatthe primary site of interaction for L- chicoric acid is the virus adsorptionstage rather than the integrase.67

68.
• The structure of the HIV-1 integrase core domain complexed with theinhibitor 5CITEP [1-(5-chloroindol- 3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)propenone] has been described as a platform for the structure-based designof novel HIV-1 integrase inhibitors.CONHNNNHO NHCl5CITEP• Diketo acid containing aromatics.68

70.
• There are number of diketo acids such a L-708,906 (29) and L-731,988(30) as inhibitors of the integrase-mediated strand transfer reaction (whichis responsible for the covalent linkage of the viral DNA 3’ ends to thecellular DNA).• The diketo acid derivative 29 and 30 were also found to inhibit HIV-1replication in cell culture .• The proviral DNA integration is indeed the target of action for the diketoacids in cell culture.NFO OOOHL-731,98830OO OOOHOL-708,90629 70

71.
• S-1360 (31) actually represents the first integrase inhibitor to reach clinicalstudies.• S-1360 would inhibit the HIV-1 integrase at an IC50 of 20 nM and theHIV-1 replication at an EC50 of 140 nM while its CC50 would be 110 μM,thus achieving a therapeutic index of almost 1000, the highest selectivity.• The mechanism of action of the diketo acids may be based on aninteraction between the carboxylate group of the diketo acids or theisosteric heterocycle in the two other compounds and metal ion(s) in theactive site of the integrase, resulting in a functional sequestration of thesecritical metal cofactors.OO OHFNNHNS-13603171

72.
• Diketo acids could be classified into two groups: Those similarly potent in the presence of magnesium and Those potent in manganese and relatively ineffective in the presence ofmagnesium.• Both the aromatic and the carboxylic or tetrazole functions of the diketoacids determine their metal-chelating selectivity.• Starting from 30, several additional 4-aryl-2,4-dioxobutanoic acidderivatives have been described as HIV-1 integrase inhibitors.• Also, new azido-containing aryl diketo acids have been described as HIV-1integrase inhibitors capable of conferring antiviral protection in HIV-infected cells.72

73.
• 8-hydroxy[1,6]-naphthyridines.Cause Inhibition of the strand transfer reaction of the integration process.• The naphthyridine shown (32) inhibits strand transfer catalyzed byintegrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1infection in cell culture at 0.39 μM.• While no cytotoxicity is exhibited in cell culture at e12.5 μ M, and a goodpharmacokinetic profile was displayed when dosed orally to rats.NONNOHSOO8-Hydroxy-[1,6]naphthyridine32 73

74.
• Recently, an entirely new class of HIV integrase inhibitors was 5H-pyrano- [2,3-d:-6,5-d¢]dipyrimidines (PDPs).• The most potent congener of this series, 5-(4-nitrophenyl)-2,8-dithiol-4,6-dihydroxy-5H-pyrano[2,3-d:-6,5-d’]dipyrimidine (V-165) (33), inhibitedthe replication of HIV-1 at an EC50 of 8.9 μM, which is 14-fold below thecytotoxicity threshold.NN O NNOHOHHSSHNO2Pyranodipyrimidine (PDP) (V-165)3374

75.
• At the transcriptional level, HIV gene expression may be inhibited bycompounds that interact with cellular factors (such as NF-B) that bind tothe LTR promotor and that are needed for basal-level transcription.• These compounds specifically inhibit the transactivation of the HIV LTRpromotor by the viral Tat (trans-activating) protein.• These compounds inhibit HIV-1 replication in both acutely and chronicallyinfected cells, through interference with the transcription process thatattributed to inhibition of Tat (or other transactivators).9. Transcription (Transactivation) Inhibitors9. Transcription (Transactivation) Inhibitors75

77.
• A 6-aminoquinolone, WM5 (34), was recently shown to inhibit HIV-1replication in acutely infected as well as chronically infected cells.• This aminoquinoline was found to efficiently bind to TAR RNA and toinhibit Tat mediated LTR-driven transcription.NNN NH2NCH3O OOHAminoquinolone WM53477

78.
• Recently prooved that the co transcriptional capping of HIV mRNA isstimulated by Tat and consequently its binding to the capping enzyme.• These findings implicate capping as an elongation checkpoint critical toHIV gene expression and thus corroborate that S-adenosylmethionine-dependent methylations play an important role in the Tat dependenttransactivation of transcription from LTR.• They also explain the inhibitory effects of S-adenosylhomocysteinehydrolase inhibitors, such as neplanocin A and 3-deazaneplanocin A (35),on Tat dependent transactivation and HIV replication.NXNNNH2HOOH OHX= N2 Neplanocin AX= CH: 3-Deazaneplanocin A3578

79.
• After transcription the unspliced (or partially spliced) HIV mRNA has tobe transported from the nucleus into the cytoplasm in order to be translatedto viral proteins.• This export is promoted by the HIV-1 Rev (regulator of expression of viralproteins).• Nuclear export of Rev is mediated by its leucine-rich nuclear export signal(NES). NES uses the export factor CRM1 to export viral mRNA from thenucleus to the cytoplasm.This process can be blocked by a smallmolecular- weight molecule, PKF 050-638 (36), that specifically inhibitsCRM1-NES complex formation and, hence, Rev-mediated nuclear export.NNNClNH2OCH3OPKF 050-6383679

82.
• The most active congener from this series, JPL-133, has an EC50 of 0.05μg/mL against HIV-1 and a selectivity index of approximately 760 in cellculture.• For other pyridine oxides such as JPL-32 and JPL-88, experimentsrevealed a postintegration step in the HIV replicative cycle as the mostlikely target of action.• The mode of action of JPL-32 appeared to be reminiscent of that of K-37because JPL-32, like K-37, was active in both acutely and chronically HIV-1-infected cells.• JPL- 32 also inhibited the Tat-mediated HIV-1 mRNA transcription fromHIV-1 LTR, thus clearly indicating that its target of action is located at thetranscription transactivation level.82

85.
• The Aza-dipeptide analogue Atazanavir (39), the latest and seventh PI To be approved for clinical use, Combines a favorable resistance profile distinct from that of the other PIs, A favorable pharmacokinetic profile allowing once-daily dosing.• Nelfinavir-, Saquinavir-, and Amprenavir-resistant HIV-1 strainsremained sensitive to Atazanavir, while Indinavir- and Ritonavir-resistant viruses showed 6- to 9-fold changes in sensitivity to atazanavir.• Conversely, Atazanavir-resistant (N88S, I84V) virus, selected uponrepeated passage of the virus in the presence of the compound, remainedsensitive to Saquinavir but showed various levels of cross-resistance toNelfinavir, Nndinavir, Ritonavir, and Amprenavir.85

87.
• Upon passage of HIV-1 in the presence of 40, mutants carrying a novelactive-site mutation, A28S, emerged.• Modeling studies revealed close contact of 40 with the main chain of theprotease active-site amino acid residues D29 and D30 different from that ofthe other PIs, and this may be important for its potency, particularlyagainst drug-resistant HIV-1 variants.• TMC 114, like TMC 126, has an excellent activity profile against HIVvariants that are highly resistant to current PIs.87

89.
• During the reverse transcription process that converts the single-strandedviral RNA into double-stranded (pro)viral DNA, a RNA‚DNAheteroduplex (hybrid) is formed.• The RNA strand of this heteroduplex must be cleaved by the ribonucleaseH (RNase H) component before the remaining (-)- DNA strand can beduplicated to give the doublestranded (pro)viral DNA that is thenintegrated into the host cell genome.• RNase H has been considered as an attractive target for the developmentof new antiretroviral agents.HIV Ribonuclease H InhibitorsHIV Ribonuclease H Inhibitors89

90.
• It is feasible to specifically inhibit HIV-1 Rnase H by, for example, novelDiketo acids, such as 4-[5- (benzoylamino)thien-2-yl]-2,4-dioxobutanoicacid (42), and N-hydroxyimides such as 2-hydroxy-4H-isoquinolone- 1,3-dione (43).• In both cases, binding of the compound was (much) stronger in thepresence of Mn2+ compared to Mg2+.NOOHO2-hydroxyisoquinoline-1,3(2H,4H)-dioneOHN SO OOOH4-(5-benzamidothiophen-2-yl)-2,4-dioxobutanoic acid4290

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Inhibitors of viral entry• It is most ideal approach to inhibit HIV binding to the T-cell• It can neutralize the virus in circulation.• The initial work on vaccine development focused on iso-typic variants ofthe HIV envelope glycoprotein gp120 obtained by recombinant DNAtechniques due to concern about the safety of live/attenuated vaccines.• The gp120 glycoprotein is a coat protein, and if great care is taken, a virus-free vaccine is obtainable.• Moreover, glycoprotein gp120 is a primary target for neutralizing antibodyassociated with the first step in HIV infection.HIV vaccinesHIV vaccines91

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• Today it is facilitated the design of vaccination regimens that elicit specificimmune responses and effector mechanisms.• The importance of CD8+ CTL responses in controlling HIV and SIVviremia has led to a series of vaccine candidates that effectively inducethese responses.• gp120-derived vaccines induced little cell-mediated immunity and strongantibody response in T-cell lines, but failed to neutralize virus derived fromperipheral blood mononuclear cells.• Recombinant attenuated vaccinia virus expresses key viral envelopeprotein followed by a booster of soluble envelope protein derived fromHIV.• It produced a good humoral and CMI response and IgA antibodies inanimal models.92

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• AIDSVAX25• AIDSVAX from VaxGen Inc. is a preventive vaccine made up of syntheticgp120. Two Phase III clinical trials were initiated. Failed due to lack ofadequate protection.• DNA VACCINE26• In recent years a new type of vaccine, created from an infectious agentsDNA called DNA vaccination.• It works by insertion (and expression, triggering immune systemrecognition) into human or animal cells, of viral or bacterial DNA.• As of 2006, DNA vaccination is still experimental, but shows somepromising results.• However, the nature of the disease people infected with HIV develop onlylow titers of neutralizing antibody and that presents problem for vaccinedevelopment.93